- Non–clear cell renal cell carcinoma (RCC) comprises a heterogeneous group of tumors with distinct histologic and molecular characterization.
- Limited phase III prospective clinical trials have included patients with non–clear cell RCC, a patient population with an unmet clinical need in terms of effective systemic therapies.
- Novel treatment and therapeutic strategies must be explored in the treatment of patients with non–clear cell RCC.
Renal cell carcinoma (RCC) encompasses a broad collection of tumors with distinct histologic and molecular characteristics. Although clear cell RCC accounts for the majority of all cases, non–clear cell disease accounts for nearly 25% of RCC in some series and includes papillary RCC (15%), chromophobe RCC (5%), and multiple other rare subtypes such as collecting duct carcinoma, medullary carcinoma, translocation RCC, and unclassified RCC.1 Sarcomatoid RCC, which was once was a separate histologic subtype, is a variant that can occur in all RCC histologies and is present in approximately 15% of RCC cases.2
The initiating oncogenic event in clear cell RCC has been attributed to VHL gene inactivation. The VHL protein has multiple functions linked to tumor suppression including inhibition of hypoxia-inducible factor (HIF), which regulates angiogenesis and metabolism.3 Characterization of the function of the VHL tumor suppressor gene has resulted in significant expansion of the treatment armamentarium for patients with metastatic disease.1
However, unlike clear cell disease, the pathogenesis of the distinct entities that comprise non–clear cell RCC has been incompletely characterized. Furthermore, given the heterogeneity of this population, patients with non–clear cell disease have been largely excluded from clinical trials that would help guide the clinical management of this disease. In this work, we review the current treatment landscape for patients with non–clear cell metastatic RCC and highlight future strategies to target these specific subtypes.
Targeted Therapies in Non–Clear Cell RCC
The treatment approach for patients with non–clear cell disease has historically mirrored the treatment of patients with clear cell RCC given the dearth of treatment options. Because of the rarity and small patient numbers within the different non–clear cell subtypes, clinical trials informing the treatment of patients with non–clear cell disease have been largely limited to phase II studies, most of which were single-arm, non-randomized trials (Table 1). Recently, two randomized phase II studies have provided evidence to support the use of VEGF inhibitors over mTOR inhibitors in patients with non–clear cell RCC who are treatment naive.
The phase II ESPN trial randomly selected 73 patients with metastatic non–clear cell RCC in a 1:1 ratio to sunitinib or everolimus with crossover at the time of disease progression.5 The trial included patients who were treatment naive with papillary, collecting duct carcinoma, translocation, and unclassified RCC, in addition to patients with clear cell RCC with greater than 20% sarcomatoid features. Interim analysis of 68 patients prompted early trial closure. The trial failed to demonstrate superior efficacy of everolimus over sunitinib as first-line therapy in metastatic non–clear cell RCC (6.1 months with sunitinib and 4.1 months with everolimus, p = 0.6). In the final analysis, median overall survival (OS) was similar between arms (16.2 months with sunitinib and 14.9 months with everolimus, p = 0.18). Objective responses were seen in 9% of patients treated with first-line sunitinib and 3% of patients treated with first-line everolimus. Despite limitations of small size and heterogeneous populations, the trial concluded that everolimus was not superior to sunitinib and both agents had modest activity in non–clear cell RCC.
In the phase II RECORD-3 trial, the sequence of sunitinib followed by everolimus was compared with the sequence of everolimus followed by sunitinib in previously untreated patients with metastatic RCC.6 Although clear cell disease was predominantly enrolled, a subgroup analysis of the 66 patients with non–clear cell RCC showed a trend favoring sunitinib. PFS was 5.1 months for everolimus versus 7.2 months for sunitinib (HR 1.54, 95% CI [0.86, 2.75]). Although underpowered for definite conclusions, these results add to our data about the level of efficacy of these agents in non–clear cell RCC.
Advances in the Management of Specific Histologic Subtypes
Although the previously mentioned trials include a variety of patients with non–clear cell RCC, the pooled analysis of multiple distinct subtypes of RCC is a limitation of these studies. Several studies have been conducted in specific subsets of patients that shed some light on the management of these distinct entities. In the non-randomized phase II SUPAP study, 61 patients with papillary RCC who were treatment naive were treated with sunitinib. Median PFS was 6.6 months (95% CI [2.8, 14.8]) for patients with type 1 disease and 5.5 months (95% CI [3.8, 7.1]) for patients with type 2 disease. The median OS was 17.8 months (95% CI [5.7, 26.1]) and 12.4 months (95% CI [8.2, 16.0]), respectively, for patients with type 1 and 2 papillary RCC. The phase II RAPTOR study investigated the role of everolimus in the first-line setting and reported a median OS of 21.0 months (95% CI [11.1, 28.0]).
Although data are limited, targeted therapies can have activity in both chromophobe and unclassified RCC. A phase II study of patients with papillary and chromophobe RCC evaluated first-line treatment with either sorafenib or sunitinib.7 In total, 12 patients (23%) had chromophobe histology, three (25%) of whom achieved a response to treatment with a PFS of 10.6 months. With regard to unclassified RCC, a phase II study evaluated the efficacy of everolimus and bevacizumab in patients with non–clear cell disease.8 In the cohort of 35 patients who were treatment naive, 66% had unclassified RCC. Given the challenge of accurate pathologic designation, in this study all unclassified cases were arbitrated by an expert committee. Among 34 evaluable patients, median PFS was 11 months, and the objective response rate (ORR) was 29%. The presence of papillary features was associated with better responses.
In contrast to other RCC histologies, collecting duct carcinomas can respond to cytotoxic chemotherapy. A phase II multicenter study evaluated treatment with gemcitabine and cisplatin or carboplatin in 23 patients with metastatic collecting duct carcinoma.9 The ORR was 26%, with a median PFS of 7.1 months and median OS of 10.5 months. Adding bevacizumab to platinum-based chemotherapy has demonstrated activity in combination with chemotherapy in collecting duct carcinoma.10
Regardless of the underlying histology, patients with sarcomatoid differentiation are observed to have a more aggressive disease phenotype, with an estimated OS of 6 months to 10 months.11 Cytotoxic chemotherapy has demonstrated antitumor activity in patients with sarcomatoid RCC.12 The largest and first randomized trial for sarcomatoid RCC (ECOG 1808) randomly assigned patients 1:1 to receive treatment with sunitinib compared to sunitinib and gemcitabine.13 Preliminary data demonstrate that the ORR was 20% for the combination compared to 11%. Median PFS was 23 weeks compared to 13 weeks for patients receiving sunitinib with gemcitabine compared to sunitinib alone.
PD-1/PD-L1 Targeted Therapies in Non–Clear Cell RCC
PD-1– and PD-L1–targeting therapies have demonstrated significant activity in the treatment of metastatic clear cell RCC.14 The role of these agents in patients with non–clear cell RCC has yet to be defined. In a study of 101 patients with non–clear cell RCC, PD-L1 expression was seen in 11% of tumor cells and 56% of tumor-infiltrating mononuclear cells.15 PD-L1 positivity was associated with higher stage, higher grade, and shorter OS. A phase I study of atezolizumab, a PD-L1 monoclonal antibody, included 70 patients with RCC, of whom 10% (7 patients) had non–clear cell histology.16 The ORR of evaluable patients with clear cell histology was 15% (62 patients). Although no objective responses were seen in patients with non–clear cell histology, one patient experienced an ongoing response by immune response criteria.
These studies highlight the rationale for investigating PD-1–targeted therapies in non–clear cell disease. Several studies are currently evaluating the utility of PD-1–targeted therapies in non–clear cell RCC (Table 2). An open, multicenter, single-arm, phase II study of atezolizumab and bevacizumab is accruing patients for enrollment (NCT02724878).
MET Inhibition in Non–Clear Cell RCC
Given the biological diversity of non–clear cell RCC, integrating the clinical outcomes of the small subsets of patients with non–clear cell disease can be challenging. The responsiveness of each RCC histologic subtype to a specific therapy is driven by the disease pathogenesis. MET has been identified to be constitutionally activated in hereditary papillary RCC and a small group of sporadic papillary RCC. MET activation is involved in tumorigenesis, metastasis, and invasiveness.18 This has spawned interest in the development of MET inhibitors for patients with metastatic disease. Several MET-targeted agents in testing include foretinib, savolitinib, and cabozantinib.
The largest study to date investigated the efficacy of foretinib, a multitargeted tyrosine-kinase inhibitor that targets MET, VEGF, and other receptors.19 In this phase II study of 74 patients with papillary RCC, the ORR was 13.5%, median PFS was 9.3 months, and median OS was 70.0% at 1 year. The presence of germline MET mutations or MET aberrations in the tumor (e.g., MET amplification, gain of chromosome 7, or somatic mutations) was highly predictive of a response to treatment.
Cabozantinib, a multitargeted tyrosine-kinase inhibitor against MET and VEGF, has recently demonstrated improvements over everolimus in ORR (17% vs. 3%), PFS (median 7.4 months vs. 3.9 months, HR 0.51, 95% CI [0.41, 0.62]), and OS (median 21.4 months vs. 16.5 months, HR 0.66, 95% CI [0.53, 0.83]) in patients with advanced, previously treated clear cell RCC.20 For patients with papillary RCC, the efficacy of cabozantinib, crizotinib, or savolitinib will be evaluated in the phase II PAPMET study (NCT02761057). Another phase II study will evaluate the efficacy of savolitinib in papillary RCC (NCT02127710).
Non–clear cell RCC represents a heterogeneous group of distinct disease entities. Patients with non–clear cell RCC have historically been underrepresented in clinical trials, and there is a need for further prospective studies exploring current and novel agents in this patient population. Novel therapeutic strategies based on the underlying disease pathology, such as MET inhibition in papillary RCC and immunotherapy with PD-1/PD-L1 in a variety of patients with non–clear cell RCC and patients with sarcomatoid differentiation, must be evaluated.
About the Authors: Dr. Harshman is an assistant professor of medicine at Harvard Medical School and the co-director of the Kidney Cancer Center at Dana-Farber/Brigham and Women’s Cancer Center. She is the principal investigator of the PROSPER RCC study. Dr. McKay is a medical oncologist who has transitioned from the Dana-Farber Cancer Institute to the University of California, San Diego, where she is an assistant professor of medicine focused on genitourinary cancers. Dr. Choueiri is the director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Chair in Medicine at Harvard Medical School.